Abstract

Background: Desmoid fibromatosis (DF) is a type of fibrous tumor that rarely metastasizes but often recurs locally. Cyclooxygenase-2 (COX-2) has been shown to be expressed in DF lesions, although its involvement in DF recurrence is unknown. We investigated the association between COX-2 expression and DF recurrence using immunohistochemistry.

Patients and Methods: Cases of DF treated in our hospital between March 2000 and December 2012 were reviewed. We used immunohistochemistry to identify COX-2 expression in resected specimens from these cases. The relationship between recurrence and age, sex, duration of disease, size of tumor, tumor site, spontaneous pain, inflammation, and COX-2 expression was studied.

Results: In the ten included cases (mean age, 55.2 y; 5 male and 5 female patients), we found that COX-2 expression was significantly associated with DF recurrence (p=0.01).

Conclusion: Our findings indicate that COX-2 is involved in recurrence of DF.

Keywords

Introduction

Desmoid fibromatosis (DF) is a locally invasive, relatively rare
mesenchymal neoplasm that develops from the connective
tissue, fascia, and aponeurosis of skeletal muscle [1]. Although
it is non-metastatic, morbidity due to local complications and
the local recurrence rate after resection is high, ranging from
20%-40% [2]; It arises in numerous locations, but most often
in the limbs, waist, scapula, and the trunk, including the
abdominal cavity [3].

DF accounts for approximately 0.03% of all soft tissue tumors
[4]. In sporadically arising cases, approximately 7.5% of DF
patients have a history of Familial Adenomatous Polyposis
(FAP) and have an 800-fold increased risk of developing DF
compared to the general population [5]. DF affects a wide
range of ages, but it is most common among those between 10
and 40 y of age [1-3]. In the paediatric population, it arises
equally in both sexes, and is predominantly abdominal [2,3].
Between puberty and 40 y old, tumors are most common in
women, and predominantly arise in the abdominal wall [6,7].
Later in adulthood, the distribution between abdominal and
extra-peritoneal tumors becomes more even, and the sex ratio
of affected patients tends towards parity [1,5-7].

The etiology of DF is multifactorial, with endocrine, physical
and genetic elements thought to be involved [8]. Several
factors indicate the role of estrogen in its development,
including the high incidence of pregnant women who develop
the condition, and disease regression or stabilization after
estrogen blockade [8]. Several studies have demonstrated estrogen receptor (ERβ) positivity in up to 90% of neoplasms
[2,9,10]. DF has also been reported to occur at sites of previous
surgery or blunt trauma [2,11,12]. Sporadic cases show a
mutation in the β-catenin gene on 3p21, resulting in
overexpression of β-catenin in the nucleus [13,14]. 14β-catenin
plays an important role in regulating the size of skin wounds
and mediates the action of TGF-β, which is known to promote
wound hyperplasia through proliferation of fibroblasts [13,14].
Thus, it can be assumed that DF represents partially
uncontrolled wound healing [2].

Histologically, DF is usually invasive and consists of uniform
myofibroblast sweep capsules in a high density collagen
stroma [3]. Approximately 80% of neoplasms show granular
nuclear expression of β-catenin [13,14]. Histologic differential
diagnosis is broad and encompasses a wide range of spindle
cell lesions, ranging from scarring to abdominal
gastrointestinal stromal tumors and liposarcoma with ‘low
grade’ dedifferentiation [15,16]. However, most neoplasms
resembling fibroma have specific histological diagnostic
characteristics and can be confidently diagnosed by the
absence of nuclear β-catenin immunoreactivity [13,14].

Due to the unpredictable natural history of the disease, it is
difficult to establish a treatment regimen for DF [17].
Historically, surgery was the main treatment with or without
radiation therapy [2,17]. Recently, some studies have reported
spontaneous regression and delayed illness in cases that are not
receiving treatment, and many institutions and investigators
have therefore proposed a ‘wait and see’ monitoring policy [18,19]. This strategy enables the identification of patients who
remain asymptomatic with stable illness or experience
spontaneous regression and protects this cohort from
unnecessary treatment.

Amongst these findings, there has been evidence that
cyclooxygenase-2 (COX-2) is involved in DF pathogenesis.
Some previous reports have shown that COX-2 inhibitors were
effective to treat intra-abdominal DF and that COX-2 inhibitors
reduce local progression of DF [18,20]. However, to date there
have been no reports investigating the role of COX-2 in DF
recurrence. Therefore, we conducted this study to investigate
whether COX-2 is involved in DF recurrence.

Materials and Methods

Ten cases of DF who underwent surgical treatment with a wide
margin at our hospital from March 2000 to December 2012
were reviewed. COX-2 immunostaining was performed on
excised pathological specimens from each patient using rabbit
monoclonal COX-2 antibody (1/100 dilution, GeneTex;
GTX16701). We investigated the relationship between DF
recurrence and various patient characteristics, including age,
sex, duration of disease, tumor size, site of the mass
(abdominal or extra-abdominal), presence of spontaneous pain,
presence of inflammatory response, and COX-2 expression.
We analyzed these factors using the chi-squared test. Since
anonymity was maintained, it was not necessary to obtain
informed consent from patients. This research was approved by
the Ethics Committee of Kindai University Faculty of
Medicine.

Results

In total, 10 patients with DF were included in this study. The
mean age was 55.2 y (range, 24-83 y), and there were 5 male
and 5 female patients. COX-2 expression was positive in 5 of
the 10 patients; of these, all 5 developed DF recurrence. Of the
remaining 5 patients in which COX-2 expression was negative,
none had DF recurrence. Statistical analysis identified a
significant association between COX-2 expression and DF
recurrence (p=0.01). The other patient characteristics,
including age, sex, duration of disease, site of the mass, size,
presence of pain, and presence of an inflammatory response,
were not associated with DF recurrence.

We present two representative example cases. The first case
involves a 56-y-old man who presented with left forearm pain
as a chief complaint. He noticed a lump in the left forearm 4
months prior to presenting at our hospital, but only visited the
hospital when the site became painful. The tumor size was 3 ×
4 cm. A blood test revealed a C-reactive protein level of 0.013 (mg/dl). The tumor mass underwent resection with wide
margins, and no recurrence was observed in the 2 y after
surgery. Expression of COX-2 in the excised specimens was
negative (<10 COX-2-positive cells/total tumor cells) (Figure
1A).

The second case features a 77-y-old man whose chief
complaint was the presence of a soft tissue mass in the left
elbow. He recognized a tumor in the left elbow 1 y ago at his
first hospital visit. Due to the gradual increase in size, the
patient visited his doctor, and was referred to our department.
The tumor size was measured to be 4 × 6 cm. He recognized
no spontaneous pain. A blood test revealed a C-reactive protein
level of 0.014 (mg/dl). We resected the tumor mass with wide
margins; the patient remained recurrence-free for 1 y after
surgery. Expression of COX-2 in the excised specimen was
positive (COX-2 positive: ≥ 10 COX-2-positive cells/total
tumor cells) (Figure 1B).

Figure 1: (A) Representative immunohistochemical findings from a
COX-2 negative case. No obvious expression of COX-2 can be
observed in the specimen, which is stained with hematoxylin eosin.
Magnification is 400X with a light microscope. Scale bar=100 μm;
(B) Representative immunohistochemical findings from a COX-2
positive case. Obvious expression of COX-2 can be seen in the
specimen, which is stained with hematoxylin and eosin.
Magnification is 400X with a light microscope. Scale bar=100 μ.

Case no.

1

2

3

4

5

6

7

8

9

10

Mean ± SD or n/n

P

Age

83

24

61

37

57

37

90

56

30

77

55.2 ± 21.3

0.65

Sex

Female

Male

Female

Female

Male

Female

Male

Male

Female

Male

M5/F5

0.88

Duration of disease

5 y

6 y

1 y

3 months

2 months

3 y

1 y

4 months

8 y

1 y

16.6 ± 23.3

0.67

Site

Scapula

Sacrum

Neck

Abdomen

Left upper arm

Gluteal

Right forearm

Left upper arm

Retroperitoneal

Left elbow

2 intra-abdominal, 8 extra-abdominal

0.98

Size (cm)

5 × 8

3 × 6

3 × 8

3 × 4

3 × 3

6 × 13

4 × 6

1.5 × 1.5

5×8

6×8

±

0.54

Pain

-

-

-

-

-

+

+

+

+

-

-6/+4

0.73

Inflammation in blood

-

-

-

-

-

+

-

-

-

-

-9/+1

0.61

COX-2 expression

+

+

-

-

-

+

+

+

-

-

5/5

0.01

Recurrence

+

+

-

-

-

+

+

+

-

-

5/5

0.01

Table 1. Summary of the ten cases included in the study.

Discussion

DF is known to have a high incidence of local recurrence
[2,13]. Recurrence is often problematic, as there are no clear
treatments indicated for DF recurrence [17]. We conducted an
investigation into factors involved in DF recurrence using
immunohistochemistry and discovered that COX-2 expression
was significantly associated with recurrence. This suggests that
COX-2 may be involved in the recurrence of DF.

Previous studies have shown that COX-2 is involved in DF
pathogenesis and that it can alter the progression of DF
[18,20]. The mutated form of the β-catenin gene (CTNNB1)
has also been suggested as a factor that can influence the
cellular activity of DF [13,14]. One of the roles of COX-2 is
suppression of β-catenin gene expression [13]. In the current
study, COX-2 expression was significantly associated with the
cases with recurrence, suggesting that COX-2 is in some way
involved in the DF recurrence mechanism.

Recent reports have suggested that DF should be treated using
a ‘wait and see’ policy [18,19] in which oncologists should
monitor the tumor prior to treatment with medication, such as a
COX-2 inhibitor, or resection. Interestingly, a previous case
report showed that pancreatic DF was cured using a COX-2
inhibitor [21]. Moreover, a previous pilot study also showed
that COX-2 inhibitor treatment for intra-abdominal DF was
effective [18]. These findings suggest that COX-2 inhibitors
might be a suitable option for treatment of DF. Combined with
the results from the present study, we suggest that COX-2
inhibitor would be effective for recurrence case of DF.

In conclusion, we examined whether COX-2 was associated
with recurrence of DF. We found that positive expression of
COX-2 was significantly associated with DF recurrence. We
suggest that COX-2 positive cells should be the treatment
target in future cases of DF recurrence.

Acknowledgement

We would like to thank Editage (www.editage.jp) for English
language editing.